1. Field of the Invention
The present invention relates to strains of bacteria and pharmaceutical compositions containing one or more of such strains and the use of same for preventing and treating diseases associated with or caused by an altered metabolism of bile acids.
2. Discussion of the Background
Hepatic bile is a pigmented isotonic fluid with an electrolyte composition resembling blood plasma. Major components of bile include water (82 percent), bile acids (12 percent), lecithin and other phospholipids (4 percent), and unesterified cholesterol (0.7 percent). Other constituents include conjugated bilirubin, proteins, electrolytes, mucus and the final products of hepatic transformation of drugs, hormones, etc. The liver production of bile, in basal conditions, is approximately 500-1000 ml/day.
The primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and excreted into the bile. Secondary bile acids, including deoxycholic acid (DCA) and lithocholic acid (LA), are formed in the colon as bacterial metabolites of the primary bile acids. Other bile acids, called tertiary bile acids (e.g.: ursodeoxycholic acid—UDCA), are formed in the gut following the enzymatic epimerization of —OH groups on sterol rings by the intestinal flora.
In normal bile, the ratio of glycine to taurine conjugates is about 2:1, while in patients with cholestasis, increased concentrations of sulfate and glucuronide conjugate of bile acids are often found. The intestinal microflora transforms the bile acids into different metabolites. These biotransformations include the hydrolysis of the bond between the bile acid and taurine or glycine, with formation of unconjugated or free bile acids and taurine or glycine. The unconjugated bile acids are therefore made available for the oxidation of the hydroxylic groups in positions C3, C7, and C12 and for the dehydroxylation in positions 7α and 7β. This latter transformation leads to the formation of the secondary bile acids DCA and LA. The primary bile acids, deconjugated bile not transformed, and the secondary biliary acids are reabsorbed from the gut lumen and enter the portal bloodstream, then are taken up by hepatocytes, conjugated with glycine or taurine and resecreted into the bile (enterohepatic circulation).
Normally, the bile acid pool circulates approximately 5 to 10 times daily. Intestinal absorption of the pool is about 95% efficient, so fecal loss of bile acids is in the range of 0.3 to 0.6 g/day. The fecal loss is compensated by an equal daily synthesis.
For this reason the composition of the pool of biliary acids present in the bile is the result of complex interactions occurring between the liver and the microflora enzymes.
Deconjugation activity is a characteristic shared by many bacteria, aerobes and anaerobes, but is particularly common among the obligate anaerobic bacteria, i.e. Bacteroides, Eubacteria, Clostridia, Bifidobacteria, etc. The majority of the bacteria is active against both glycine and taurine conjugates; however, some of them have a certain degree of specificity, depending on the bound amino acid and the number of hydroxides bound to the steroid nucleus. The free biliary acids obtained following the action of the bacterial hydrolases can undergo the oxidation of the hydroxide groups present at the C3, C7, and C12 positions by the hydroxysteroidodehydrogenase.
The interest in the metabolic disorders of biliary acids comes from the hypothesis that biliary acids and/or metabolites thereof are involved in the pathogenesis of some hepato-biliary and gastroenterologic diseases: biliary dyspepsia, cholelithiasis, acute and chronic hepatopathies, inflammatory diseases of the colon, etc.
Very often in literature the hydrophobicity of the bile acid is correlated with detergency; the secondary bile acids are more hydrophobic than the primary bile acids, the deoxycholic acid (DCA) being actually more detergent than the cholic acid (CA). Therefore an increased concentration of DCA in the bile may involve: a) an augmentation of the secretion of cholesterol, with increased saturation index; b) a cytotoxic effect on the liver cells.
For this reason a qualitative modification of the bile acids pattern could be a decisive factor, especially in treating the above-mentioned pathologies.
Thus, there remains a need for effective bacterial strains or compositions that, by reducing the 7α-dehydroxylase activity and at the same time deconjugation, can be used for treating and/or preventing diseases associated with metabolic disorders of the biliary acids.
No bacteria strains have been found that are capable of qualitatively modifying the bile acid pattern in such a way.